Cardiorenal Syndrome in Children With Heart Failure - Springer Link

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Concomitant cardiac and renal dysfunction has been termed the cardiorenal syndrome (CRS). This clinical condition usually manifests as heart failure.
Cardiorenal Syndrome in Children With Heart Failure Jack F. Price, MD, and Stuart L. Goldstein, MD

Corresponding author Jack F. Price, MD Department of Pediatrics (Cardiology), Baylor College of Medicine, Texas Children’s Hospital, 621 Fannin Street, MC 19345-C, Houston, TX 77030, USA. E-mail: [email protected] Current Heart Failure Reports 2009, 6:191–198 Current Medicine Group LLC ISSN 1546-9530 Copyright © 2009 by Current Medicine Group LLC

Concomitant cardiac and renal dysfunction has been termed the cardiorenal syndrome (CRS). This clinical condition usually manifests as heart failure with worsening renal function and occurs frequently in the acute care setting. A consistent defi nition of CRS has not been universally agreed upon, although a recent classification of CRS describes several subtypes depending on the primary organ injured and the chronicity of the injury. CRS may develop in adults and children and is a strong predictor of morbidity and mortality in hospitalized and ambulatory patients. The underlying physiology of CRS is not well understood, creating a significant challenge for clinicians when treating heart failure patients with renal insufficiency. This review summarizes recent data characterizing the incidence, physiology, and management of children who have heart failure and acute kidney injury.

and an increased risk of in-hospital mortality [6]. Even a modest increase in SCr (> 0.3 mg/dL) can predict mortality in patients hospitalized for heart failure [7]. Similarly, asymptomatic patients with renal insufficiency and left ventricular dysfunction are also at risk of pump failure and death [8]. The relationship of renal function and heart failure in children has not been well examined. Retrospective data have shown a high incidence of cardiac disease among children who develop renal insufficiency while hospitalized. Anecdotal experience suggests that, as in adults, worsening renal function is associated with poor outcomes in children with heart failure [9•]. A recent prospective study of children admitted to an intensive care unit (ICU) with a wide range of diseases found a low incidence of acute kidney injury (AKI) but a strong association with all-cause mortality [10•]. That study, however, included all children admitted to a pediatric ICU. A recent report from our center examined children admitted to an ICU who required mechanical ventilation and at least one vasoactive medication [11•]. We found a high incidence of AKI (82% by pediatric RIFLE [Risk, Injury, Failure, Loss, End-Stage Renal Disease] criteria) and increased mortality rate in children with more severe AKI. These studies further demonstrate our lack of understanding of the cardiorenal relationship, as cardiovascular dysfunction was found to be both a risk factor for and a complication of acute renal failure.

Introduction

Defining the Cardiorenal Syndrome

Renal insufficiency occurs commonly in adult patients with heart failure. Although the mechanisms are not fully understood, diminished cardiac function coupled with renal dysfunction, or the cardiorenal syndrome (CRS), has been observed in both the acute and chronic care settings. Decreased urine output and resultant fluid retention can aggravate heart failure symptoms and contribute to clinical deterioration. Several recent studies have demonstrated the prognostic importance of increasing serum creatinine (SCr) concentrations for predicting morbidity and mortality in adult patients with heart failure [1–3,4•,5]. Among patients hospitalized for acute decompensated heart failure (ADHF), worsening renal function is associated with longer length of hospitalization, higher in-hospital costs,

One of the greatest challenges to understanding the diagnosis and management of CRS is defi ning it. Historically, renal insufficiency in heart failure patients was attributed to a low cardiac output state causing decreased renal perfusion, or the so-called prerenal state. Recent data suggest that venous congestion may also play a significant role [12]. These hemodynamic descriptions of the cardiorenal relationship, however, fail to acknowledge the impact that acute and chronic kidney disease can have on the cardiovascular system, particularly the patient with preexisting heart failure [13]. A consistent and clear defi nition that acknowledges the bidirectional relationship of the heart and kidney has not existed until recently. Ronco et al. [14] have proposed a new classification of the CRS into five

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Table 1. Types of cardiorenal syndrome Type of CRS

Mechanism of injury

Examples

Comments

Acutely worsening cardiac function leads to AKI

Cardiogenic shock, acute decompensated HF

May lead to diuretic resistance; predicts adverse outcomes in children

Chronic HF leads to chronic kidney disease

Chronic congestive HF

Associated with increased mortality risk

AKI leads to acutely worsening cardiac function

Glomerulonephritis, acute tubular necrosis

Fluid overload, uremia, hyperkalemia, acidemia, affect cardiac function

Type 4 (chronic renocardiac syndrome)

Chronic kidney disease leads to worsening cardiac function

Chronic glomerular disease, end-stage renal disease

High risk of adverse cardiovascular events, coronary calcification

Type 5 (secondary CRS)

Systemic condition leads to cardiac and renal dysfunction

Sepsis, SLE, diabetes

No therapies yet can prevent or attenuate AKI in critically ill patients

Type 1 (acute)

Type 2 (chronic) Type 3 (acute renocardiac syndrome)

AKI—acute kidney injury; CRS—cardiorenal syndrome; HF—heart failure; SLE—systemic lupus erythematosus. (Adapted from Ronco et al. [14])

subtypes that recognize the time course, pathophysiology, and characteristics of simultaneous cardiac and renal insufficiency (Table 1).

cardiac surgery [10•]. Other causes include acute renal ischemia, nephrotoxic medications, and sepsis [9•].

CRS type 4 (chronic renocardiac syndrome) CRS type 1 (acute CRS) Type 1 CRS is characterized by an acute worsening of cardiac function that leads to AKI. Examples of acute heart failure include cardiogenic shock, ADHF, and right heart failure. This type of CRS occurs commonly and is generally well-recognized. It is estimated that nearly half of pediatric patients with decompensated heart failure will develop worsening renal function while hospitalized [15•]. Among this group of patients, preexisting chronic renal insufficiency frequently predisposes to AKI [16].

In type 4 CRS, a chronic kidney disease leads to worsening cardiac function, ventricular hypertrophy, or an increased risk of cardiovascular events. In children, acquired kidney disease, such as glomerulonephritis, or anatomic abnormalities, such as hypoplasia or dysplasia, may lead to chronic renal failure. Adult patients with chronic kidney disease are at increased risk of cardiovascular disease or its exacerbation. The overall risk of mortality is 10- to 20-fold higher in patients with end-stage renal disease than in patients without chronic renal failure [17]. Cardiovascular risk in children with chronic kidney disease is not well understood.

CRS type 2 (chronic CRS) In type 2 CRS, chronic congestive heart failure leads to progressive chronic kidney disease. Nearly 25% of patients with chronic heart failure have a glomerular fi ltration rate (GFR) lower than 44 mL/min [2]. Dries et al. [8] found that even moderate degrees of renal insufficiency (estimated creatinine clearance < 60 mL/min) are independently associated with an increased risk for all-cause mortality (RR, 1.41) in patients with chronic heart failure [8]. The investigators speculated that, rather than simply being a marker of the severity of underlying disease, the adequacy of renal function may determine patients’ abilities to compensate in heart failure and that improving renal function may delay disease progression.

CRS type 3 (acute renocardiac syndrome) In type 3 CRS, AKI leads to an acute cardiac disorder, such as worsening heart failure or arrhythmia. Examples of AKI include acute glomerulonephritis and acute tubular necrosis. The most common causes of acute renal failure in children requiring intensive care therapies are hemolytic uremic syndrome, oncologic pathologies, and

CRS type 5 (secondary CRS) Type 5 CRS is manifested by combined cardiac and renal insufficiency that is caused by systemic disorders. This is an uncommon form of CRS and may occur in adults with diabetes, amyloidosis, or sarcoidosis. In children, disorders that may be associated with type 5 CRS include systemic inflammatory response syndrome, oncologic disease, or systemic lupus erythematosus.

Acute Kidney Injury in Children Diagnosis and management of AKI constitutes one of the most important roles of the pediatric nephrologist in an ICU. Proper management of pediatric AKI requires an understanding of the multiple pathophysiologic and clinical events that lead to renal injury, the life-threatening and non–life-threatening effects of AKI, and when conservative versus more aggressive management is indicated. Until recently, very little research has focused on the cause of AKI in children. As such, defi nitions used in various studies varied substantially.

Cardiorenal Syndrome in Children

Epidemiology and definition The epidemiologic importance of AKI as a public health problem is clear. Evidence shows that even a modest reduction (increase in SCr by 0.3 mg/dL) in the renal function of adult [18] and pediatric hospitalized [15] patients is a risk factor for morbidity and mortality. Few data exist to accurately describe the incidence of pediatric AKI, though hospital and pediatric ICU-acquired AKI appears to be increasing [19]. This difference may be the result of changing diagnostic profi les in the past 10 to 20 years, increasing use of more invasive management strategies, and higher acuity of illness among hospitalized pediatric patients. Studies examining AKI have used differing defi nitions, varying from an increase in SCr or decrease in urine output to a requirement for dialysis. When renal replacement therapy (RRT) is required, the strictest defi nition of AKI is used and the incidence of AKI in the pediatric ICU is less than 2% [10,19]. When less strict defi nitions are used, such as a doubling of SCr, the incidence of AKI ranges from 1% to 21%, depending on patient population characteristics [10,11,19]. Infants undergoing cardiopulmonary bypass procedures have been studied more extensively and the AKI incidence is fairly consistent in the range of 10% to 25% [20–22]. In 2004, a common AKI consensus definition was proposed by the Acute Dialysis Quality Initiative: the RIFLE criteria [23]. The adult-derived RIFLE definition was modified, and then applied and validated in pediatric patients and renamed the pediatric RIFLE (pRIFLE) criteria. These modified criteria stratify AKI from mild (RIFLE R, “risk”) to severe (RIFLE F, “failure”) based on changes in SCr or estimated creatinine clearance (cCCl) and urine output. The first study that defined AKI using the pRIFLE criteria found that AKI occurred in 82% of the most critically ill children admitted to a pediatric ICU [11]. The pRIFLE criteria have been validated independently by another group in Europe [24], and AKI incidence was similar in their ICU. Similar to studies in adults [25–27], AKI defined by these criteria was an independent risk factor for mortality and increased length of stay. Although the pRIFLE criteria are not currently applicable in the clinical setting for medical decision-making, they provide a multidimensional research tool to assist with AKI descriptive and outcome studies. Further epidemiologic research using this common definition will contribute to understanding the true incidence of mild-to-severe AKI in a wide range of geographic and diagnostic patient populations.

Cardiac Disease and Acute Kidney Injury in Children Unlike their adult counterparts, very few data have been published in children examining the simultaneous functions of the heart and kidney. Cardiovascular disease and renal insufficiency certainly are not uncommon among critically ill pediatric patients. Bailey et al. [10•] reported the incidence of AKI at 4.5% in 1047 children hospitalized in

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an intensive care unit. In their study, 61% of AKI (defined as a doubling of baseline serum creatinine) cases occurred secondary to extrarenal etiologies, such as hemato-oncologic diseases, sepsis, and respiratory failure. Nearly 20% of children carried a principal diagnosis of cardiac disease. The incidence of AKI among patients admitted for cardiac disease was quite low (3%). However, 6% of all patients in their cohort were found to have cardiac dysfunction and, among those, approximately 1 in 5 were diagnosed with AKI while hospitalized. Cardiac dysfunction was associated with the development of AKI (RR, 6.5; P < 0.001) but was not included in multivariate analysis. Independent risk factors for AKI included thrombocytopenia (OR, 6.3); age older than 12 years (OR, 4.9); hypoxemia (OR, 3.2); hypotension (OR, 3.0); and coagulopathy (OR, 2.7). The authors determined that 45% of patients with AKI subsequently developed cardiac dysfunction or cardiac arrest as a complication of their kidney disease. Overall mortality was 11 times higher in patients with AKI than in those without AKI (27.3% vs 2.4%; P < 0.001). Hui-Stickle et al. [9•] reported on the epidemiology of AKI in children at our center where cardiac transplantation and surgery for congenital heart disease are performed. In this retrospective study, 248 children were discharged after treatment of 254 cases of AKI (GFR < 75 mL/min/1.73 m2) during a 3.5-year period. Primary renal disease accounted for only 17 (7%) cases whereas 43 (17%) episodes occurred in patients who had a cardiac comorbid condition. Ischemia in the presence of congenital heart disease was the most common cause of AKI in newborn infants (27% of cases). Hypoplastic left heart syndrome was the most prevalent type of congenital heart disease associated with AKI in neonates. Sixty-five percent of children whose AKI was attributable to congenital heart disease survived. Nearly two thirds of those patients who survived to discharge recovered complete renal function. Only one study has evaluated combined heart failure and renal dysfunction in children [15•]. We described our observations of worsening renal function (WRF) in 73 consecutive patient hospitalizations with a primary diagnosis of ADHF. The etiologies for ADHF were heterogenous but the majority of children had been diagnosed with dilated cardiomyopathy and 58% had a history of preexisting heart failure. WRF was defined as an increase in SCr of ≥ 0.3 mg/dL at any time during hospitalization. Renal failure at the time of admission was uncommon in this cohort but SCr subsequently increased in 82% (median increase, 0.2 mg/dL) and WRF occurred during 48% of hospitalizations. These data are consistent with reports in adults with left ventricular systolic dysfunction and heart failure [26,27]. Using the same SCr minimum increase of 0.3 mg/dL, Gottlieb et al. [4•] reported a similar frequency of WRF in adults of 39%. In this cohort of children, WRF was found to be an independent predictor of death or the need for mechanical circulatory assistance during hospitalization (OR, 10.2) and was associated with a longer observed length of stay (33 ± 30 d vs 18 ± 25 d). We speculated that WRF may

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signal worsening heart failure and allow clinicians to risk stratify patients who might be considered for mechanical support earlier in their hospital course, before the onset of multiorgan dysfunction.

Acute Kidney Injury After Surgery for Congenital Heart Disease Depending on the defi nition used, AKI is common, occurring in approximately 10% to 50% of children following surgery for congenital heart disease [21,28,29]. Cardiopulmonary bypass, a low cardiac output state after surgery, residual cardiovascular lesions, potentially nephrotoxic medications, and aggressive postoperative diuresis can contribute to renal ischemia–reperfusion injury [21]. Adverse outcomes related to AKI after cardiac surgery occur frequently. In adults, AKI following cardiac surgery is associated with a number of morbidities, such as the need for dialysis and prolonged ICU and hospital stay, as well as increased in-hospital mortality and decreased long-term survival [30–32]. Children who develop AKI after surgery for congenital heart disease have longer hospital stays and higher mortality rates than children without AKI [33]. As noted previously, adverse clinical outcomes can be associated with even a modest rise in SCr. An elevation in SCr, however, is an inadequate marker of AKI because creatinine clearance must decrease by as much as 50% before a rise in SCr can be detected. This failure to identify renal dysfunction early in the course of AKI has provided impetus to search for new biomarkers that can herald renal insufficiency earlier than a change in SCr. Potential urinary and plasma markers in both adults and children include kidney injury molecule (KIM)-1, N-acetyl-β-D-glucosaminidase (NAG), and neutrophil gelatinase-associated lipocalin (NGAL). Concentrations of NGAL increase soon after renal ischemic injury and can be easily measured in the plasma and urine [22,33]. A point-of-care enzymelinked immunosorbent assay for plasma NGAL can predict early AKI, morbidity and mortality after surgery for congenital heart disease [33]. Sensitivity and specificity for predicting AKI were high for the 2-hour measurement with an area under the curve of 0.96. Moreover, the diagnosis of AKI using an SCr measurement was delayed by 2 to 3 days after the surgery. Earlier detection of AKI may lead to improved outcomes in children. A recent large, multicenter trial showed that earlier initiation of renal replacement therapy is associated with improved survival in children with multiorgan dysfunction, lending support to a change in clinical practice that advocates earlier initiation of renal mechanical support [34].

Pathophysiology of Cardiorenal Syndrome in Heart Failure The physiologic interaction of the heart and kidney is complex and not well understood, although it is recognized

that disease of one organ system frequently complicates the other. Renal insufficiency occurring in heart failure patients is usually attributed to diminished cardiac output and renal perfusion, or a prerenal state. This explanation of concomitant cardiorenal dysfunction oversimplifies the complex interrelationship of these two organs and fails to acknowledge the neurohormonal and vasoreactive elements of decompensated heart failure. In type I CRS, worsening cardiac function leads to acute renal injury and kidney dysfunction. Arterial underfi lling causes decreased baroreceptor activation in the left ventricle, carotid sinus, and afferent arterioles of the kidney [35]. Signals from the brain then activate efferent sympathetic nervous system pathways, which provoke upregulation of the neurohormonal system. Sympathetic nervous system stimulation of the peripheral vasculature and renal arteries, as well as activation of the renin-angiotensin-aldosterone system and arginine vasopressin, serve as adaptive mechanisms for restoring blood pressure and vascular volume. Simultaneously, vasoconstriction and diminished sodium excretion are countered by the release of endogenous vasodilators, such as nitric oxide, bradykinin, and natriuretic peptides. Over time, however, these adaptive mechanisms become maladaptive, leading to elevated systemic vascular resistance, fluid overload, and decreased renal perfusion (Fig. 1). Loop diuretics, standard fi rst-line therapy for decompensated heart failure, can contribute to decreased renal blood flow and worsening prerenal azotemia. The use of intravenous diuretics, such as furosemide, can activate the renin-angiotensin-aldosterone system, leading to further systemic vasoconstriction and fluid retention [36]. Worsening renal function may then ensue during diuretic therapy [37]. In adults with worsening heart failure, intravenous furosemide can augment urine output, but at the expense of GFR [4•]. Worsening renal function usually occurs early in the course of hospitalization in both adults [38] and children [15]. We found that the median time for development of AKI in children hospitalized with heart failure was 3.5 days, usually a time of aggressive diuresis and fluid shifts. The AKI that occurs during the early treatment of decompensated heart failure, however, cannot be attributed to diuretic therapy alone [39•]. Ljungman et al. [40] found that renal blood flow is usually preserved until the cardiac index drops below 1.5 L/min/m 2 and standard intravenous therapies for advanced heart failure, such as vasodilators and diuretics, usually reduce fi lling pressures without compromising cardiac output [1]. Furthermore, extravascular fluid usually shifts to the vascular space in volume-overloaded patients without compromising intravascular volume [39•]. Hence, the “dried out” heart failure patient who remains volume overloaded during diuretic therapy may have other etiologies for AKI. Additional factors (eg, persistent or aggravated systemic vasoconstriction; use of potentially nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs or contrast

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Figure 1. Pathophysiology of cardiorenal syndrome in heart failure.

agents; renal artery stenosis; infection; and renal vein hypertension) may lead to AKI during the treatment of heart failure [41]. Firth et al. [42] demonstrated that high central venous pressure was associated with reduced GFR, whereas cardiac output and mean arterial pressure were preserved. Increased abdominal pressure is also associated with renal dysfunction in ADHF [12]. Diuretic resistance is a common problem for the clinician when treating heart failure. It usually occurs when pulmonary congestion persists despite high-dose loop diuretics, continuous infusions, or combination diuretic therapy. Diuretic resistance is more likely to occur in patients with preexisting renal insufficiency and, when coupled with AKI and fluid overload, may be extremely difficult to manage [39•]. Because renal perfusion may be reduced in heart failure patients, delivery of the diuretic to the tubules is also diminished. Chronic diuretic therapy can lead to hypertrophy of the distal tubular cells associated with increased sodium reuptake due to the blockade of sodium and potassium transport [43]. Severe hypoalbuminemia may also lead to perceived diuretic resistance. Albumin binds to loop diuretics and is necessary for delivery of the diuretic to the proximal tubule. Replacement of albumin in patients with abnormally low concentrations may be required to optimize diuretic effect [39]. In ambulatory HF patients, diuretic resistance may be due to decreased oral absorption and medication noncompliance.

Table 2. Strategies for management of cardiorenal syndrome in children with advanced heart failure Monitor for worsening renal function Daily weight measurements Strict recording of fluid balance Daily blood urea nitrogen and serum creatinine concentrations Central venous pressure monitoring Optimize heart failure therapy Maintain adequate blood pressure Consider milrinone or systemic vasodilator to augment stroke volume Consider cardiac resynchronization therapy Consider low-dose dopamine Enhance diuresis Increase dose of loop diuretic Transition diuretic dosing to continuous infusion Add a thiazide diuretic Consider nesiritide infusion Consider fenoldopam infusion Consider vasopressin antagonists/adenosine antagonists* Renal replacement therapies Peritoneal dialysis Consider venovenous ultrafiltration* *No data in children with advanced heart failure.

Management of Cardiorenal Syndrome in Children Because AKI occurs commonly in children who are hospitalized with decompensated heart failure, this cohort should be monitored closely for evidence of worsening renal function, especially early in their treatment course, when AKI is most likely to occur. This includes the strict

recording of fluid balance, daily weight measurements, and at least daily blood urea nitrogen (BUN) and creatinine concentrations while administering intravenous diuretics. Invasive monitoring of central venous pressure may be helpful in some situations (Table 2).

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Standard management strategies for CRS in pediatric heart failure do not exist as the syndrome remains poorly understood and treatments are largely empiric and anecdotal. Therapies should be individualized, taking into account a history of preexisting renal insufficiency, whether a patient is receiving potentially nephrotoxic medications, infection, and abnormalities of renal structure such as renal artery stenosis [39•]. Unfortunately, independent risk factors for predicting the development of CRS in children are not known at this time. When evaluating a child with CRS and decompensated heart failure, it is essential to assess the optimization of heart failure therapy. Treatments that may increase systemic vascular resistance, such as dopamine and epinephrine infusions, may only exacerbate renal hypoperfusion and should be reserved for the patient in cardiogenic shock or impending shock. The use of systemic vasodilators or an inotrope with additional vasodilatory properties, such as milrinone, may unload the heart without compromising renal blood flow. Milrinone toxicity can occur, however, in children with significantly reduced creatinine clearance and should therefore be dosed appropriately. Other therapies such as cardiac resynchronization, transfusion of packed red cells for anemia, and use of low “renal-dose” dopamine may also be considered, although there is no evidence on which to base these recommendations. The clinician’s fi rst instinct is to discontinue intravenous diuretics when the SCr begins to rise and urine output decreases, thinking that the patient has reached a euvolemic or hypovolemic state and that additional diuresis may only exacerbate the worsening renal function. Although it is certainly possible to deplete intravascular volume in heart failure patients, most patients remain fluid overloaded during this time. In children who remain symptomatic with evidence of extravascular fluid retention and possible diuretic resistance, diuresis may be enhanced by using a continuous infusion of loop diuretics rather than bolus injections. Luciani et al. [44] demonstrated that among critically ill neonates and infants who have undergone cardiac surgery, a continuously infused loop diuretic afforded lower total diuretic dosing with comparable urine output to bolus dosing and lesser fluctuations in urine output and need for fluid replacement. A meta-analysis by Salvador et al. [45] showed that urine output was modestly improved in adult heart failure patients receiving continuous infusions of diuretic compared with patients receiving intermittent dosing. The data were insufficient, however, to reliably assess the relative benefits of the two treatment regimens. Nesiritide (recombinant human B-type natriuretic peptide) is a systemic vasodilator with diuretic and natriuretic properties. It has been used for the treatment of ADHF in both adults and children, providing improved hemodynamics and increased urine output while avoiding some of the adverse side effects of inotropic agents

[46,47]. Low-dose nesiritide may provide a renal protective effect in adult patients with decompensated heart failure and renal dysfunction. Riter et al. [48] reported on a retrospective study examining the safety of low-dose nesiritide (0.005 μg/kg/min) and found that, unlike standard dosing (0.01 μg/kg/min), systolic blood pressure did not decrease during infusions of the lower dose of nesiritide [48]. Similar urine output was achieved at lower doses of furosemide in the low-dose group compared with the standard-dose group, and renal function improved with a decrease in SCr and BUN by the end of therapy. The authors speculated that this renal-enhancing strategy may have resulted from the preservation of systolic blood pressure during the therapy. At our institution, we have used nesiritide in normotensive children with ADHF. We reported our experience with 143 nesiritide infusions in 63 consecutive children who were hospitalized in the intensive care unit for symptomatic heart failure [47]. Continuous infusions of nesiritide (0.01–0.03 μg/kg/min) were associated with decreased heart rate, increased urine output, neurohormonal attenuation, and improved renal function after 72 hours of therapy. Only two infusions had to be discontinued for hypotension. Despite apparent safety and efficacy in small studies, nesiritide may be associated with worsening renal function. In a meta-analysis of five randomized, controlled studies comparing nesiritide with either placebo or control for decompensated heart failure, standard dose nesiritide increased the risk of worsening renal function (RR, 1.52; P = 0.003) [49]. Further investigation of the safety and efficacy of nesiritide is now being performed in appropriately powered trials. Administering a different type of diuretic in combination with loop diuretics may also augment urine output. In a study of 20 adult patients with severe heart failure and diuretic resistance while receiving high-dose furosemide, the addition of hydrochlorothiazide resulted in improved urine output and decreased creatinine clearance [50]. Hypokalemia was an important side effect of this strategy and occurred in the majority of the patients. Fenoldopam is a dopamine-1 receptor antagonist with renal vasodilatory and natriuretic properties. We have administered fenoldopam to critically ill children to enhance urine output and protect against AKI [51]. Continuous infusions have resulted in improved diuresis and stable SCr without the need for escalation of inotropic agents. Peritoneal dialysis is another alternative for fluid removal in diuretic-resistant heart failure patients. We have used this therapy in a small number of children with low creatinine clearance who remain fluid overloaded with ascites despite treatment with various types and escalating doses of diuretic agents. Anecdotally, this has allowed us to remove excess fluid, which has sometimes led to improved kidney function and urine output. We may have relieved renal vein congestion by decompressing the abdomen, thus allowing for improved diuresis.

Cardiorenal Syndrome in Children

Conclusions CRS is a complicated and poorly understood clinical condition seen commonly in adults and children hospitalized with heart failure. A bidirectional relationship appears to exist with one diseased organ system aggravating the other. When AKI occurs in heart failure patients, the risk of morbidity and mortality is increased and treatment options are limited. Few data have been reported on the incidence, management, and outcomes of CRS in pediatrics, but it appears that combined cardiac and renal dysfunction may be associated with poor outcomes in children hospitalized with decompensated heart failure. Further epidemiologic and treatment strategy studies should be performed.

Disclosure No potential confl icts of interest relevant to this article were reported.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

Weinfeld MS, Chertow GM, Stevenson LW, et al.: Aggravated renal dysfunction during intensive therapy for advanced heart failure. Am Heart J 1999, 138:285–290. 2. Hillege HL, Girbes AR, de Kam PJ, et al.: Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation 2000, 102:203–210. 3. Mahon NG, Blackstone EH, Francis GS, et al.: The prognostic value of estimated creatinine clearance alongside functional capacity ambulatory patients with chronic congestive heart failure. J Am Coll Cardiol 2002, 40:1106–1113. 4.• Gottlieb SS, Abraham W, Butler J, et al.: The prognostic importance of different defi nitions of worsening renal function in congestive heart failure. J Card Fail 2002, 8:136–141. This article demonstrated that even modest increases in serum creatinine can predict mortality and increased length of stay among adult patients hospitalized for heart failure treatment. 5. Forman DE, Butler J, Wang Y, et al.: Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol 2004, 43:61–67. 6. Krumholtz HM, Chen YT, Vaccarino V, et al.: Correlates and impact on outcomes of worsening renal function in patients 65 years of age with heart failure. Am J Cardiol 2000, 85:1110–1113. 7. Smith GL, Vaccarino V, Kosiborod M, et al.: Worsening renal function: what is a clinically meaningful change in creatinine during hospitalization with heart failure? J Card Fail 2003, 9:13–25. 8. Dries DL, Exner DV, Domanski MJ, et al.: The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol 2000, 35:681–689. 9.• Hui-Stickle S, Brewer ED, Goldstein SL: Pediatric ARF epidemiology at a tertiary care center from 1999 to 2001. Am J Kidney Dis 2005, 45:96–101. In this retrospective review of 254 acute renal failure episodes in a pediatric tertiary referral center, data showed that pediatric acute renal failure characteristics have changed from primary renal disease to renal insufficiency secondary to systemic disease.

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Bailey D, Phan V, Litalien C, et al.: Risk factors of acute renal failure in critically ill children: a prospective descriptive epidemiological study. Pediatr Crit Care Med 2007, 8:29–35. A prospective study of more than 1000 children hospitalized that determines the incidence rate, identifies risk factors, and describes the clinical outcome of AKI in the pediatric ICU. 11.• Akcan-Arikan A, Zappitelli M, Loftis LL, et al.: Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 2007, 71:1028–1035. This was the fi rst study to use the modified pediatric RIFLE criteria for defi ning AKI in hospitalized children. Using these criteria, AKI was determined to independently predict intensive care, length of stay, and risk of death. 12. Mullens W, Zuheir A, Francis GS, et al.: Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009, 53:589–596. 13. Berl T, Henrich W: Kidney-heart interactions: epidemiology, pathogenesis, and treatment. Clin J Am Soc Nephrol 2006, 1:8–18. 14. Ronco C, Haapio M, House A, et al.: Cardiorenal syndrome. J Am Coll Cardiol 2008, 52:1527–1539. 15.• Price JF, Mott AR, Dickerson HA, et al.: Worsening renal function in children hospitalized with decompensated heart failure: evidence for a pediatric cardiorenal syndrome? Ped Crit Care Med 2008, 9:279–284. In this prospective study of AKI in children hospitalized for decompensated heart failure, AKI was independently associated with death and need for mechanical circulatory support. 16. Fonarow GC, Stough WG, Abraham WT, et al.: Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF registry. J Am Coll Cardiol 2007, 50:768–777. 17. Johnson DW, Craven AM, Isbel NM: Modification of cardiovascular risk in hemodialysis patients: an evidencebased review. Hemodial Int 2007, 11:1–14. 18. Chertow GM, Burdick E, Honour M, et al.: Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005, 16:3365–3370. 19. Vachvanichsanong P, Dissaneewate P, Lim A, McNeil E: Childhood acute renal failure: 22-year experience in a university hospital in southern Thailand. Pediatrics 2006, 118:e786–e791. 20. Chan KL, Ip P, Chiu CS, Cheung YF: Peritoneal dialysis after surgery for congenital heart disease in infants and young children. Ann Thorac Surg 2003, 76:1443–1449. 21. Skippen PW, Krahn GE: Acute renal failure in children undergoing cardiopulmonary bypass. Crit Care Resusc 2005, 7:286–291. 22. Mishra J, Dent C, Tarabish R, et al.: Neutrophil gelatinaseassociated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005, 365:1231–1238. 23. Bellomo R, Ronco C, Kellum JA, et al.: Acute renal failure-defi nition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the acute dialysis quality initiative (ADQI) group. Crit Care 2004, 8:R204–212. 24. Plotz FB, Bouma AB, van Wijk JA, et al.: Pediatric acute kidney injury in the ICU: an independent evaluation of pRIFLE criteria. Intensive Care Med 2008, 34:1713–1717. 25. Abosaif NY, Toba YA, Heap M, et al.: The outcome of acute renal failure in the intensive care unit according to RIFLE: model application, sensitivity, and predictability. Am J Kidney Dis 2005, 46:1038–1048. 26. Bibbins-Domingo K, Lin F, Vittinghoff E, et al.: Renal insufficiency as an independent predictor of mortality among women with heart failure. J Am Coll Cardiol 2004, 44:1593–1600. 27. McAlister FA, Ezekowitz J, Tonelli M, et al.: Renal insufficiency and heart failure: Prognostic and therapeutic implications from a prospective cohort study. Circulation 2004, 109:1004–1009.

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Decompensated Heart Failure: Pathophysiology and Treatment

Nguyen MT, Dent CL, Ross GF, et al.: Urinary aprotinin as a predictor of acute kidney injury after cardiac surgery in children using aprotinin therapy. Pediatr Nephrol 2008, 23:1317–1326. 29. Beger RD, Holland RD, Sun J, et al.: Metabonomics of acute kidney injury in children after cardiac surgery. Pediatr Nephrol 2008, 23:977–984. 30. Loef BG, Epema AH, Smilde TB, et al.: Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival. J Am Soc Nephrol 2005, 16:195–200. 31. Lok CE, Austin PC, Wanh H, Tu JV: Impact of renal insufficiency on short- and long-term outcomes after cardiac surgery. Am Heart J 2004, 148:430–438. 32. Mangano CM, Diamondstone LS, Ramsay JG, et al.: Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. The Multicenter Study of Perioperative Ischemia Research Group. Ann Intern Med 1998, 128:194–203. 33. Dent CL, Ma Q, Dastrala S, et al.: Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study. Crit Care 2007, 11:R127. 34. Goldstein SL, Somers MJ, Baum MA, et al.: Pediatric patients with multi-organ dysfunction syndrome receiving continuous renal replacement therapy. Kidney Int 2005, 67:653–658. 35. Schrier RW, Abraham WT: Hormones and hemodynamics in heart failure. N Engl J Med 1999, 34:577–585. 36. Bayliss J, Norell M, Canepa-Anelson et al.: Untreated heart failure: clinical and neuroendocrine effects of introducing diuretics. Br Heart J 1987, 57:17–22. 37. Butler J, Forman DE, Abraham WT, et al.: Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J 2004, 147:331–338. 38. Gottlieb SS, Brater DC, Thomsas I, et al.: BG9719 (CVT124), and A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation 2002, 105:1348–1353. 39.• Liang KV, Williams AW, Greene EL, Redfield MM: Acute decompensated heart failure and the cardiorenal syndrome. Crit Care Med 2008, 36:S75–S88. This article provides a thorough review of the risk factors, pathophysiology, and treatment of cardiorenal syndrome in adults.

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Ljungman S, Laragh JH, Cody RJ: Role of the kidney in congestive heart failure: relationship of cardiac index to kidney function. Drugs 1990, 39(Supp 4):10–21. Heywood JT: The cardiorenal syndrome: lessons from the ADHERE database and treatment options. Heart Fail Rev 2004, 9:195–201. Firth JD, Raine AE, Ledingham JG: Raised venous pressure: a direct cause of renal sodium retention in oedema? Lancet 1988, 1:1033–1035. Swan SK: Diuretic strategies in patients with renal failure. Drugs 1994, 48:380–385. Luciani GB, Nichani S, Chang AC, et al.: Continuous versus intermittent furosemide infusion in critically ill infants after open heart operations. Ann Thorac Surg 1997, 64:1133–1139. Salvador DR, Rey NR, Ramos GC, Punzalan FE: Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. Cochrane Database Syst Rev 2005, 3:CD003178. Colucci WS, Elkayam U, Horton DP, et al.: Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide study group. N Engl J Med 2000, 343:246–253. Jefferies JL, Price JF, Denfield SW, et al.: Safety and efficacy of nesiritide in pediatric heart failure. J Cardiac Fail 2007, 13:541–548. Riter HG, Redfield MM, Burnet JC, Chen HH: Nonhypostensive low-dose nesiritide has differential renal effects compared with standard-dose in patients with acute decompensated heart failure and renal dysfunction. J Am Coll Cardiol 2006, 47:2334–2335. Sackner-Bernstein JD, Skopicki HA, Aaronson KD: Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005, 111:1487–1491. Dormans TP, Gerla PG, Russel FG, Smits P: Combination diuretic therapy in severe congestive heart failure. Eur Heart J 1996, 17:1867–1874. Moffett BS, Mott AR, Nelson DP, et al.: Renal effects of fenoldopam in critically ill pediatric patients: a retrospective review. Pediatr Crit Care Med 2008, 9:403–406.